title: The STIM1 CTID domain determines access of SARAF to SOAR to regulate Orai1 channel function.
abstract: Ca(2+) influx by store-operated Ca(2+) channels (SOCs) mediates all Ca(2+)-dependent cell functions, but excess Ca(2+) influx is highly toxic. The molecular components of SOC are the pore-forming Orai1 channel and the endoplasmic reticulum Ca(2+) sensor STIM1. Slow Ca(2+)-dependent inactivation (SCDI) of Orai1 guards against cell damage, but its molecular mechanism is unknown. Here, we used homology modeling to identify a conserved STIM1(448-530) C-terminal inhibitory domain (CTID), whose deletion resulted in spontaneous clustering of STIM1 and full activation of Orai1 in the absence of store depletion. CTID regulated SCDI by determining access to and interaction of the STIM1 inhibitor SARAF with STIM1 Orai1 activation region (SOAR), the STIM1 domain that activates Orai1. CTID had two lobes, STIM1(448-490) and STIM1(490-530), with distinct roles in mediating access of SARAF to SOAR. The STIM1(448-490) lobe restricted, whereas the STIM1(490-530) lobe directed, SARAF to SOAR. The two lobes cooperated to determine the features of SCDI. These findings highlight the central role of STIM1 in SCDI and provide a molecular mechanism for SCDI of Orai1.
authors.affiliation: Epithelial Signaling and Transport Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Archana
authors.initials: A
authors.lastname: Jha
authors.forename: Malini
authors.initials: M
authors.lastname: Ahuja
authors.forename: József
authors.initials: J
authors.lastname: Maléth
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Moreno
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Yuan
authors.forename: Min Seuk
authors.initials: MS
authors.lastname: Kim
authors.forename: Shmuel
authors.initials: S
authors.lastname: Muallem
mesh_terms: D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D017124:Conserved Sequence; D057809:HEK293 Cells; D006801:Humans; D052139:Intracellular Calcium-Sensing Proteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D000071740:ORAI1 Protein; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion; D000071737:Stromal Interaction Molecule 1; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship
chemical_list: D015220:Calcium Channels; D052139:Intracellular Calcium-Sensing Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C572578:SARAF protein, human; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D002118:Calcium